Method for treatment of recurrent paroxysmal neuropsychiatric

ABSTRACT

Recurrent paroxysmal neuropsychiatric disorders selected from (1) acute dystonic reactions, (2) seizure disorders and (3) panic disorders may be treated by means of aerosol inhalation of (1) anticholinergic and/or antihistaminic agents, (2) benzodiazepines and (3) antihistaminic agents, respectively.

This is a continuation of application Ser. No. 07/801,491, filed on Dec.2, 1991, now abandoned.

This invention relates to methods for the treatment of recurrentparoxysmal neuropsychiatric disorders of rapid onset and brief duration,such as acute dystonic reactions, seizure disorder and panic disorder.

Acute Dystonic Reactions are a common, frightening, extremelyuncomfortable and potentially fatal side effect of neurolepticmedications. These reactions are characterized by acute muscularrigidity and cramping (sometimes of sufficient severity to dislocatejoints, obscure vision, or to obstruct the airway). Neurolepticmedications are widely used throughout the world and are the mainstay ofpharmacologic treatment of schizophrenia, mood disorders with psychoticcomponents, Tourette's syndrome, agitated, explosive behavior,intractable hiccups, and intractable vomiting. Of patients takingneuroleptic medication, 11.9% will experience acute dystonic reactions.

Panic Disorder is a psychiatric syndrome characterized by extremeanxiety or terror which is accompanied by severe muscle tension andautonomic hyperactivity. It occurs in discrete episodes of abrupt onset("panic attacks") and is a recurrent condition.

Seizure disorders may be of the generalized tonic clonic (grand mal),partial motor, or psychomotor type. Generalized convulsive seizures arecharacterized by violent involuntary contractions of the muscles.Prolonged seizures (status epilepticus) may damage cerebral tissue. Inapproximately half of cases generalized convulsive seizures are precededby a warning sensation called an "aura" that may be recognized by thepatient or his family. Focal seizures may begin in an extremity whilethe patient is awake and alert and may progress over a matter of secondsor minutes to full blown generalized convulsion (Jacksonian March).

While the causes of these three conditions are different, their symptomshave in common an abrupt onset with rapid escalation of symptoms and arelatively brief duration. Each disorder may be preceded by briefwarning symptoms (an "aura") before the rapid escalation of symptomsbegins. Consequently, their symptomatic treatment may in both casesbenefit from an agent with extremely rapid onset.

Some agents have been shown to be effective in the prevention ofrecurring panic disorder attacks. Examples of this are reported in U.S.Pat. No. 4,980,354, Cairns, et al.; U.S. Pat. No. 4,962,128, Doogan, etal.; U.S. Pat. No. 4,783,477, Lammintausta et al.; U.S. Pat. No.4,782,060, Kurtz et al.; U.S. Pat. No. 4,634,703, Kurtz et al.; U.S.Pat. No. 4,510,153 Coleman. They are administered orally, by injection,or by ingestion so as to maintain in the patient's body a therapeuticdrug concentration which lessens the frequency of these events. However,such techniques do not completely eliminate their occurrence. Moreover,long term prophylactic use of such agents exposes the patient to a highrisk of physical and psychological withdrawal symptoms followingdiscontinuance of long-term use.

Currently, the only effective way to interrupt an acute dystonicreaction is to administer an intramuscular or an intravenous injectionof diphenhydramine or an anticholinergic agent such as benztropine orbiperiden. This normally requires the patient, if not currentlyhospitalized, to be taken to a hospital emergency room. A substantialdelay usually occurs after onset of symptoms before medication can beinjected because time is lost calling for help (if the patient canspeak) being transported to the hospital, being checked into thehospital, and being evaluated. During this lapse between onset ofsymptoms and initiation of treatment the patient may experience extremediscomfort and interference in breathing, swallowing and speaking.

The most effective pharmacological means of aborting a panic attack isan intramuscular or intravenous injection of a benzodiazepine orantihistamine. This also normally requires the patient to be taken to ahospital emergency room. Again, a substantial period of time usuallyelapses after onset of symptoms before medication can be injectedbecause time is lost attaining assistance, being transported to thehospital, being checked into the hospital, and being evaluated. Duringthis lapse between onset of symptoms and initiation of treatment, thepatient may experience terrifying anxiety and severe physicaldiscomfort.

The only currently available means of interrupting a seizure orpreventing a seizure once a warning aura has appeared is an injection ofa benzodiazepine.

These methods of treatment are not entirely satisfactory. Oraladministration of drugs does not result in a rapid response and it isinadvisable if the patient has difficulty swallowing (as is often thecase). It is very difficult to administer an injection to someone whohas fallen into uncontrollable, perhaps violent motor activity. Also,failure to terminate an attack in its early stages risks physical andemotional harm to the patient and the patient's family.

Accordingly, it is desired to provide a method of treating acute panicdisorder and acute dystonic reaction which is fast acting, can beadministered by the patient and which can terminate the event before itssymptoms become severe.

According to the present invention, this is achieved by administering aneffective dose of a therapeutic agent by aerosol inhalation. This may bedone by the patient, without assistance, at the first sign of an attack,or aura. By this technique, the therapeutic agent can be applied to therespiratory mucosa which is highly vascularized and permeable to theseagents. Prompt intervention in this manner allows the rapid absorptionand action of these drugs and the early termination of the event,sometimes even before its symptoms become serious.

Panic attacks can be treated in this manner by administeringantihistamines such as diphenhydramine and hydroxyzine.

Acute dystonic reactions are advantageously treated by administeringantihistamines or anticholinergics (such as benztropine, biperiden ortrihexyphenidyl). Benztropine and diphenhydramine are generallypreferred.

Seizures may be interrupted at the first sign of an aura or after thefull seizure begins by administering benzodiazepines such as diazepam orlorazepam. Diazepam is preferred.

The method of the present invention may be practiced in the followingmanner:

A pharmaceutical grade of a suitable benzodiazepine, antihistamine, oranticholinergic active ingredient can be dissolved in a non-toxicsolubilizing substance, such as ethyl alcohol in sufficient proportionto maintain the solubility of the active ingredient in the propellant.

Appropriate adjuvants may be added to improve absorption through thenasal or pulmonary mucosa. Compounds reported to be effective for thispurpose include surfactants such as sodium glycocholate, saponin,polyoxyethylene-9-laurylether and sodium taurodihydrofusidate. Compoundssuitable for use as propellants in aerosolized medical preparationsinclude ethyl chloride, butane, propane, dichlorodifluoromethane,dichlorotetrafluoroethane, and trichloromonofluoromethane.

A suitable vapor pressure for such a device is between 15 and 60 poundsper square inch at room temperature (20-25 degrees centigrade).

There are three commonly used and effective means of deliveringmedication into the lungs or nasal cavity: 1) aerosolized metered dosepumps, 2) manual metered dose pumps, and 3) metered dose spray-producingsqueeze bottles. Each of these is effective in providing for the rapidabsorption of medicinal compounds into the blood stream. The choice ofdelivery system will depend on the preference or physical limitations ofthe individual patient. In unconscious patients experiencing seizures,however, the aerosolized metered dose pump connected to a close fittingplastic mask covering the nose and mouth (such as is commonly used toadminister oxygen) is the most effective delivery system.

The propellant is combined with the mixture of active ingredientdissolved in the ethyl alcohol (or other suitable solubilizingsubstance) and surfactant or other absorption-enhancing compound in anaerosol canister containing a metered valve suitable for delivering asingle predetermined volume. Aerosol containers such as this may becomposed of any non-toxic substance capable of withstanding sufficientinternal pressure and are widely utilized commercially. They generallyoperate by filling a well of predetermined volume with theself-propelling composition which is dispersed as an aerosol. Thesubstance mixtures and propellant may be mixed before they are placedinto the aerosol canister or placed into the canister separately, bycommercially available pressure or cold-filled methods. When thecanister is depressed, a mouthpiece or nasal adapter will deliver apredetermined volume of the contents, containing a predetermined dosageof the active ingredient into the pulmonary or nasal cavity,respectively as the patient takes a deep inhalation.

Appropriate predetermined dosages to be delivered with each actuationare described below. These dosages are based on Food and DrugAdministration recommendations for parenteral or oral use of thesemedications.

Illustrative Examples of Formulations Useful for Interruption of PanicAttacks

    ______________________________________                                        Example A:                                                                    20%     diphenhydramine                                                       20%     anhydrous ethanol                                                     25%     dichlorodifluoromethane                                               25%     trichloromonofluoromethane                                            12.5    mg. diphenhydramine is delivered per actuation                        Example B:                                                                    20%     hydroxyzine                                                           30%     anhydrous ethanol                                                     25%     dichlorodifluoromethane                                               25%     trichloromonofluoromethane                                            12.5    mg. hydroxyzine is delivered by actuation                             ______________________________________                                    

Illustrative Examples of Formulations Useful for Interruption of AcuteDystonic Reactions

    ______________________________________                                        Example A:                                                                    05%     benztropine                                                           25%     anhydrous ethanol                                                     35%     dichlorodifluoromethane                                               35%     trichloromonofluoromethane                                            2.0     mg. benztropine is delivered per actuation                            Example B:                                                                    05%     trihexyphenidyl                                                       25%     anhydrous ethanol                                                     35%     dichlorodifluoromethane                                               35%     trichloromonofluoromethane                                            2.0     mg. trihexyphenidyl is delivered per actuation                        Example C:                                                                    05%     biperiden                                                             25%     anhydrous ethanol                                                     35%     dichlorodifluoromethane                                               35%     trichloromonofluoromethane                                            2       mg. biperiden delivered per actuation                                 Example D:                                                                    20%     diphenhydramine                                                       30%     anhydrous ethanol                                                     25%     dichlorodifluoromethane                                               25%     trichloromonofluoromethane                                            12.5    mg. diphenhydramine is delivered per actuation                        ______________________________________                                    

Illustrative Examples of Formulations Useful

for Interruption of Seizures

    ______________________________________                                        Example A:                                                                    25%       diazepam                                                            35%       anhydrous ethanol                                                   20%       dichlorodifluoromethane                                             20%       trichloromonofluoromethane                                          5.0       mg. diazepam delivered per actuation                                Example B:                                                                    05%       lorazepam                                                           25%       anhydrous ethanol                                                   35%       dichlorodifluoromethane                                             35%       trichloromonofluoromethane                                          1.0       mg. lorazepam delivered per actuation                               Example C:                                                                    05%       clonazepam                                                          25%       anhydrous ethanol                                                   35%       dichlorodifluoromethane                                             35%       trichloromonofluoromethane                                          0.5       mg. clonazepam delivered per actuation                              ______________________________________                                    

The mixture of active ingredient dissolved in ethyl alcohol (or othersuitable solubilizing substance) and surfactant (or otherabsorption-enhancing compounds) can be placed in a pump canistercontaining a metered valve suitable for delivering a singlepredetermined volume. Canisters such as this may be composed of anynon-toxic substance capable of withstanding sufficient internal pressureand are widely utilized commercially. They generally operate by fillinga well of predetermined volume with the composition which is dispersedas a suspension by depressing the manual pump. To operate the manualpump spray unit, the pump if first primed by depressing the pump severaltimes. Subsequently, when the pump is depressed the mouthpiece adapteror nasal adapter will deliver a predetermined volume of the contents,containing a predetermined concentration and dosage of the "activeingredient" into the lungs or nasal cavity as the patient takes a deepinhalation. Appropriate predetermined dosages of active ingredient to bedelivered with each actuation are identical to those described for theaerosolized metered dose pump.

The mixture of active ingredient dissolved in ethyl alcohol (or othersuitable solubilizing substance) and surfactant (or otherabsorption-enhancing compound) can be placed in a flexible squeezebottle suitable for delivering a single predetermined volume. Squeezebottles such as this may be composed of any flexible non-toxic substancesuch as plastic that is capable of withstanding sufficient internalpressure and are widely utilized commercially. When the squeeze bottleis squeezed the mouthpiece or nasal adapter will deliver a predeterminedvolume of the contents, containing a predetermined concentration anddosage of the "active ingredient" into the nasal cavity as the patienttakes a deep inhalation. Appropriate predetermined dosages of activeingredient to be delivered with each actuation are identical to thosedescribed for the aerosolized metered dose pump.

I claim:
 1. A process for the treatment of recurrent paroxysmalneuropsychiatric disorders of brief duration selected from acutedystonic reaction and seizure disorder which comprises the step ofadministering to a patient who has experienced symptoms that indicate anepisode of the disorder is about to occur and before onset of theepisode, by means of aerosol inhalation, an efficacious dose of atherapeutic agent which,(i) for acute dystonic reaction is selected fromanticholinergics and antihistamines, and (ii) for seizure disorder is abenzodiazepine.
 2. The process of claim 1, wherein the episode is acutedystonic reaction and the therapeutic agent is selected from the groupconsisting of at least about 2.0 mg of benztropine and at least about12.5 mg of diphenhydramine.
 3. The process of claim 1, wherein theepisode is seizure disorder and the therapeutic agent is at least about5.0 mg of diazepam.
 4. The process of claim 1, wherein the therapeuticagent is administered by aerosol inhalation through the nose.
 5. Theprocess of claim 1, wherein the therapeutic agent is administered byaerosol inhalation through the mouth.
 6. A process for the treatment ofrecurrent paroxysmal neuropsychiatric disorders of brief durationselected from among panic disorder, acute dystonic disorder and seizuredisorder which comprises the step of administering to a patient who isexperiencing symptoms of such disorder, by means of aerosol inhalation,an efficacious dose of a therapeutic agent which(i) for acute panicdisorder is an antihistamine, (ii) for acute dystonic reaction isselected from anticholinergics and antihistamines, (iii) for seizuredisorder is a benzodiazepine.
 7. The process of claim 6, wherein theepisode is acute dystonic reaction and the therapeutic agent is selectedfrom the group consisting of at least about 2.0 mg of benztropine and atleast about 12.5 mg of diphenhydramine.
 8. The process of claim 6,wherein the episode is panic disorder and the therapeutic agent isselected from the group consisting of at least about 12.5 mg ofdiphenhydramine and at least about 12.5 mg of hydroxyzine.
 9. Theprocess of claim 6, wherein the episode is seizure disorder and thetherapeutic agent is at least about 5.0 mg of diazepam.
 10. The processof claim 6, wherein the therapeutic agent is administered by aerosolinhalation through the nose.
 11. The process of claim 6, wherein thetherapeutic agent is administered by aerosol inhalation through themouth.